Abstract
Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-alpha production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8(Sluggish) mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-alpha and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ethylnitrosourea*
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Genetic Predisposition to Disease*
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Herpesviridae Infections / genetics
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Herpesviridae Infections / immunology
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Interferon Type I / antagonists & inhibitors*
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Interferon Type I / biosynthesis
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Listeriosis / genetics
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Listeriosis / immunology
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MAP Kinase Kinase Kinases / genetics*
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MAP Kinase Kinase Kinases / physiology
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Male
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Muromegalovirus / immunology
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Mutagenesis* / immunology
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / physiology
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RNA Splicing / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology
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Streptococcal Infections / enzymology*
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Streptococcal Infections / genetics
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Streptococcal Infections / immunology*
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Streptococcus agalactiae / immunology*
Substances
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Interferon Type I
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Proto-Oncogene Proteins
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MAP Kinase Kinase Kinases
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Map3k8 protein, mouse
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Ethylnitrosourea